1. Field of the Invention
The present application relates to synthesis of entecavir and intermediates thereof.
2. Description of the Related Arts
Entecavir (Baraclude®) is a cyclopentyl guanosine nucleoside analogue, or called a novel carbocyclic 2′-deoxyguanosine analogue, which has shown potent and selective activity against Hepatitis B Virus (HBV). Entecavir was developed by Bristol-Myers Squibb (BMS) and it was approved by the United States Food and Drug Administration in March 2005. The chemical name of entecavir is 2-amino-1,9-dihydro-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one and is used as a mono hydrate form with molecular formula of C12H17N5O4, which corresponds to a molecular weight of 295.29 g/mol. Entecavir is a white to off-white powder, slightly soluble in water (2.4 mg/mL), and the pH of the saturated solution in water is 7.9 at 25° C.±0.5° C.
WO2004052310A2 (BMS patent application) discloses processes (see BMS Schemes 15 and 16, which are disclosed at pages 41 and 44 of WO2004052310A2 and shown below, hereinafter “BMS process”) for the preparation of entecavir. WO2004052310A2 also discloses preparation of intermediates having silyl protecting groups by using Corey lactone as a starting material.


Despite prior disclosure of processes for the preparation of entecavir and intermediates thereof, there is still a need for a convenient process of making entecavir as well as its intermediates with desired purity and yield.